Clinical progression rates among untreated HIV-infected patients and the clinical responses to antiretroviral therapy among treated patients are highly variable and only partially explained by plasma HIV RNA levels, suggesting that factors other than the extent of viral replication play a role in HIV pathogenesis. In vitro and animal models suggest that HIV causes widespread activation of CD4+ and CD8+ T cells, resulting in CD4+T cell depletion and immunodeficiency, and suggest a primary role of T cell activation in HIV pathogenesis. While higher levels of T cell activation are associated with more rapid clinical progression in HIV-infected patients, the biologic and clinical determinants of T cell activation in HIV infection remain poorly defined. In seeking a K23 Award, I am interested in exploring the role of virologic factors, host factors, and co-infections in determining T cell activation levels in HIV infection. I propose the following specific aims among HIVinfected patients: (1) to assess the association between virologic factors - including the extent of proviral HIV DNA in circulating cells, the extent of low-level viral replication, replicative capacity, and co-receptor tropism - and T cell activation; (2) to assess the association between host factors - including HLA haplotype and CCR5 polymorphisms - and T cell activation; (3) to assess the association between asymptomatic shedding of CMV and T cell activation; and (4) to assess whether valganciclovir treatment decreases T cell activation levels in a randomized controlled trial among HIV and CMV co-infected patients with sub-optimal immunologic responses to antiretroviral therapy. Understanding the potential causes of T cell activation may help identify targets for future immune-based interventions for many HIV-infected patients with suboptimal immunologic responses to antiretroviral therapy. To achieve these aims, I have assembled a mentoring committee of internationally recognized scientists with strong track records in translational research. These mentors span several relevant disciplines, including clinical research methods (Drs. Deeks and Jacobson), epidemiology and biostatistics (Dr. Martin), immunology (Dr. McCune), and virology (Dr. Wong). Their mentorship, as well as a focused training and research plan facilitated by a K23 award, will help me achieve my goal of developing an independent career in clinic-based translational research, focusing on questions relevant to the pathogenesis of HIV infection.